Cytomegaloviruses (CMVs) are common pathogens and are members of the xcex2 subgroup of the herpesvirus family. CMV is a slow replicating, species-specific complex DNA virus found in most mammals. CMV has adopted subtle evolutionary strategies for evading the immune system of an infected host, while disseminating through the host tissues.
The genome (230 kb) of human CMV (HCMV) includes a long and short unique region (UL and US, respectively), each of which is flanked by inverted repetitions. The entire HCMV genome has been sequenced (Chee, M. S., et al. (1990) Curr. Top. Microbiol. Immunol. 154:125-169) and appears to contain over 200 open reading frames.
One of these open reading frames is referred to as US28, which encodes a protein (also xe2x80x9cUS28xe2x80x9d) that acts as a functional receptor for certain human and viral chemokines (see, e.g., Gao and Murphy, 1994, J Biol Chem. 269:28539-42). Upon infection of a cell by CMV, US28 is expressed on the surface of the infected cell and becomes capable of responding to chemokines in the environment. Three other open reading frames called US27, UL33 and UL78 encode for proteins having homology to US28 as shown in Table 1 below.
Chemokine receptors such as US28 generally are G protein coupled receptors. Structurally these receptors have seven transmembrane segments that loop in and out of the cell membrane, as well as an intracellular tail that is coupled to a G protein signal transducing molecular complex.
The chemokines themselves constitute a subgroup of a larger class of signaling proteins and have the ability, among other things, to promote cellular migration (Zlotnik et al. (1999) Crit. Rev. Immunol. 19:1-47). The chemokines generally are divided into four groups based upon the arrangement of certain cysteine residues within the protein that can form disulfide bonds. One class of chemokines is the beta chemokines that are characterized by having two adjacent cysteines; this structure is referred to in shorthand form simply as CC. The beta chemokines are involved in attraction of monocytes and leukocytes. The alpha chemokines, in contrast, have a single amino acid separating the two cysteine residues, and thus their structure is designated as CXC. These chemokines are primarily involved in attracting polymorphonuclear cells. The fractalkines or delta-chemokines constitute a third class of chemokines and tend to be cell bound molecules. The two cysteines in this class are separated by three amino acid residues, a structure designated as CX3C. This class of chemokines are expressed at high levels in the brain; some evidence indicates that the fractalkines are involved in neuron-glial cell interactions (see, e.g., Harrison, et al. (1998) Proc. Natl. Acad. Sci. U.S.A. 95:10896-10901; and Nishiyori, A. et al. (1998) FEBS Lett. 429:167-172). The US28 receptor of HCMV is characterized in part by its very strong affinity for fractalkine. The structure of the final class of chemokines is simply referred to as C (also gamma-chemokines), because these chemokines contain only a single N-terminal cysteine involved in a disulfide bond. The chemokine receptors have varying specificity for the different classes of chemokines. Some chemokine receptors can bind chemokines from different classes.